Atezolizumab and Cobimetinib or Idasanutlin in Participants With Stage IV or Unresectable Recurrent Estrogen Receptor Positive Breast Cancer

NCT ID: NCT03566485

Last Updated: 2021-08-11

Basic Information

• Recruitment Status: TERMINATED
• Clinical Phase: PHASE1/PHASE2
• Total Enrollment: 12 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2018-07-10
• Study Completion Date: 2020-12-10

Brief Summary

This phase I/II trial studies the side effects and best dose of idasanutlin when given together with atezolizumab, and to see how well atezolizumab and cobimetinib or idasanutlin work in treating participants with stage IV estrogen-receptor positive (ER+) breast cancer, or ER+ breast cancer that has come back (recurrent) and cannot be removed by surgery (unresectable). Monoclonal antibodies, such as atezolizumab, may interfere with the ability of tumor cells to grow and spread. Cobimetinib and idasanutlin may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Giving atezolizumab with cobimetinib or atezolizumab with idasanutlin may work better in treating participants with estrogen-receptor positive breast cancer.

Detailed Description

PRIMARY OBJECTIVES:

I. To determine the safety and tolerability of atezolizumab and idasanutlin in patients with estrogen receptor positive (ER+) metastatic breast cancer (mBC) (Phase I).

II. To determine the anti-tumor effect of atezolizumab and cobimetinib or idasanutlin in patients with ER+ mBC (Phase II).

SECONDARY OBJECTIVES:

I. To determine the anti-tumor duration of effect of atezolizumab and cobimetinib or idasanutlin in patients with ER+ mBC (Phase II).

II. To determine the safety and tolerability of atezolizumab and cobimetinib or idasanutlin in patients with ER+ mBC (Phase II).

EXPLORATORY OBJECTIVES:

I. To evaluate if CD8+ T cells are enhanced in the tumor with either MEK or MDM2 inhibition (Phase II).

II. To evaluate if MHC-I/II and/or PD-L1 expression is enhanced with MEK inhibition (Phase II).

III. To evaluate if T cell chemotractants (CCL5, CXCL9,10,11,13) are upregulated upon MDM2 antagonism (Phase II).

IV. To determine if baseline or changes in PDL1 expression, MHC expression, presence of tumor infiltrating lymphocytes, neoantigen expression/ mutation burden (using ribonucleic acid [RNA]-and whole exome sequencing), CCL5, CXCL9, CXCL10, CXCL11, and CXCL13 correlate with clinical outcome (Phase II).

V. To determine if immunological activity of MEK inhibition can be tracked noninvasively using Zr^89-atezolizumab (Phase II).

OUTLINE: This is a phase 1, dose-escalation study of idasanutlin followed by a phase II study. Participants are assigned to 1 of 2 arms.

ARM I: Participants with TP53 gene mutation receive atezolizumab intravenously (IV) over 60 minutes starting with day 15 of course 1 and then on days 1 and 15 of subsequent courses, and cobimetinib orally (PO) daily on days 1-21. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.

ARM II: Participants without TP53 gene mutation receive atezolizumab IV over 60 minutes starting with day 15 of course 1 and then on days 1 and 15 of subsequent courses, and idasanutlin PO daily on days 1-5. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, participants are followed for 28 days.

Conditions

Stage III Breast Cancer; Stage IIIA Breast Cancer; Stage IIIB Breast Cancer; Stage IIIC Breast Cancer; Stage IV Breast Cancer; Estrogen Receptor-positive; HER2/Neu Negative

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

Phase 2 (atezolizumab, cobimetinib)

Participants with TP53 gene mutation receive atezolizumab IV over 60 minutes starting with day 15 of course 1 and then on days 1 and 15 of subsequent courses, and cobimetinib PO daily on days 1-21. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.

Group Type: EXPERIMENTAL

Atezolizumab

Intervention Type: DRUG

Given by IV

Cobimetinib

Intervention Type: DRUG

Given by mouth

Phase 1b - Atezolizumab 840mg IV + Idasanutlin 100mg PO

Group Type: EXPERIMENTAL

Atezolizumab

Intervention Type: DRUG

Given by IV

Idasanutlin

Intervention Type: DRUG

Given by mouth

Interventions

Atezolizumab

Given by IV

Intervention Type: DRUG

Cobimetinib

Given by mouth

Intervention Type: DRUG

Idasanutlin

Given by mouth

Intervention Type: DRUG

Eligibility Criteria

Inclusion Criteria

• Re-enrollment of a subject that has discontinued the study as a pre-treatment screen failure (i.e. a consented patient who did not receive study drugs) is permitted. If re-enrolled, the subject must be re-consented. Only the screening procedures performed outside of protocol-specified timing must be repeated.

Exclusion Criteria

• Prior therapy with anti-PD-L1 and anti-PD1 antibodies, MEK inhibitors or MDM2 antagonists.
• No more than 3 lines of chemotherapy in the metastatic setting
• No concurrent anticancer therapy. Required washout from prior therapy:

• Endocrine therapy: no required wash-out
• Chemotherapy: 14 days
• Major surgery: 14 days (provided wound healing is adequate)
• Radiation: 7 days
• Investigational/Biologic Therapy (half -life ≤ 40 hours): 14 days
• Investigational/Biologic Therapy (half -life > 40 hours): 28 days
• Use of corticosteroids or immunosuppressive medication is exclusionary, except the following in the absence of active autoimmune disease:

• Subjects are permitted the use of corticosteroids with minimal systemic absorption (e.g. topical, ocular, intra-articular, intranasal, and inhaled);
• Systemic corticosteroids at physiologic doses ≤10 mg/day of prednisone or equivalent are permitted;
• Adrenal replacement steroid doses including doses > 10 mg daily prednisone are permitted;
• A brief (less than 3 weeks) course of corticosteroids for prophylaxis (e.g. CT scan premedication against contrast dye allergy) or for treatment of non-autoimmune conditions (e.g. delayed-type hypersensitivity reaction caused by a contact allergen) is permitted.
• Previous malignant disease other than breast cancer within the last 5 years, with the exception of basal or squamous cell carcinoma of the skin, cervical carcinoma in situ, or low-risk cancers considered curatively treated (i.e. complete remission achieved at least 2 years prior to first dose of study drugs AND additional therapy not required while receiving study treatment).
• All subjects with brain metastases, except those meeting the following criteria:

• Brain metastases that have been treated locally and are clinically stable for at least 2 weeks prior to enrollment
• No history of intracranial or spinal cord hemorrhage
• No evidence of interim CNS disease progression
• Metastasis to the midbrain, pons, and medulla
• No ongoing neurological symptoms that are related to the brain localization of the disease (sequelae that are a consequence of the treatment of the brain metastases are acceptable.
• Subjects must be either off steroids or on a stable or decreasing dose of ≤ 10 mg daily prednisone (or equivalent)
• Receipt of any organ transplantation including allogeneic stem-cell transplantation.
• Significant acute or chronic infections including, among others:

• Known history of testing positive for human immunodeficiency virus (HIV), or acquired immunodeficiency syndrome (AIDS).
• Active tuberculosis
• Positive test for hepatitis B virus (HBV) surface antigen (and/or core antibody) and/or confirmatory hepatitis C virus (HCV) RNA (if anti-HCV antibody tested positive).
• Active autoimmune disease with reasonable possibility of clinically significant deterioration when receiving an immunostimulatory agent:

• Subjects with Type 1 diabetes mellitus, vitiligo, psoriasis, hypo- or hyperthyroid disease not requiring immunosuppressive treatment are eligible.
• Subjects requiring hormone replacement with corticosteroids are eligible if the steroids are administered only for the purpose of hormonal replacement and at doses ≤ 10 mg or 10 mg equivalent prednisone per day.
• Administration of steroids through a route known to result in a minimal systemic exposure (topical, intranasal, intro-ocular, or inhalation) are acceptable.
• Interstitial lung disease that is symptomatic or which may interfere with the detection or management of suspected drug-related pulmonary toxicity.
• Uncontrolled asthma [defined as having 3 or more of the following features of partially controlled asthma within 28 days prior to starting study treatment: Daytime symptoms more than twice per week, any limitation of activities, any nocturnal symptoms/awaking, need for reliever/rescue inhaler more than twice per week, or known lung function (PEF or FEV1) without administration of a bronchodilator that is < 80% predicted or personal best (if known)].
• Current symptomatic congestive heart failure (New York Heart Association > class II), unstable cardiac arrhythmia requiring therapy (e.g. medication or pacemaker), unstable angina (e.g. new, worsening or persistent chest discomfort), or uncontrolled hypertension (systolic > 160 mmHg or diastolic > 100mmHg). Or any of the following occurring within 6 months (180 days) prior to first dose of study drugs: Myocardial infarction, coronary/peripheral artery bypass graft, cerebrovascular accident or transient ischemic attack. (Use of antihypertensive medication to control blood pressure is allowed.)
• Concurrent treatment with a non-permitted drug (refer to prohibited medication list) as well as foods or supplements that are strong or moderate CYP3A4 enzyme inducers or inhibitors. Any of the above has to be discontinued at least 7 days prior to Cycle 1/ Day 1 of study treatment.
• Requirement of anticoagulant therapy with oral vitamin K antagonists such as Coumadin (warfarin). Low-dose anticoagulants for the maintenance of patency in a central venous access device or the prevention of deep vein thrombosis or pulmonary embolism is allowed. Therapeutic use of low molecular weight heparin is allowed provided patients are safely able to interrupt it prior to biopsy procedures.
• Persisting toxicity related to prior therapy that has not reduced to Grade 1 [National Cancer Institute Common Toxicity Criteria for Adverse Events (NCI CTCAE) version 5.0]; however, alopecia and sensory neuropathy Grade ≤ 2 are acceptable and Grade ≤ 2 non-hematological toxicities well controlled with medical management are allowed (for example: hypomagnesemia well controlled on magnesium replacement).
• Known severe (Grade ≥ 3 NCI-CTCAE) hypersensitivity reactions to monoclonal antibodies, or history of anaphylaxis.
• Vaccination within 28 days of the first dose of study drugs and while on trial is prohibited, except for administration of inactivated vaccines (for example, inactivated influenza vaccine).
• Pregnant or breastfeeding females.
• Known current alcohol or drug abuse
• Prisoners or subjects who are involuntarily incarcerated.
• Known psychiatric condition, social circumstance, or other medical condition reasonably judged by the patient's study physician to unacceptably increase the risk of study participation; or to prohibit the understanding or rendering of informed consent or anticipated compliance with scheduled visits, treatment schedule, laboratory tests and other study requirements.
• Known risk factors for ocular toxicity, consisting of any of the following (Cobi arm only):

• presence of serous retinopathy within 6 months of protocol enrollment
• presence of retinal vein occlusion (RVO) within 6 months of protocol enrollment

• Minimum Eligible Age: 18 Years
• Eligible Sex: FEMALE
• Accepts Healthy Volunteers: No

Sponsors

Genentech, Inc.

INDUSTRY

Sponsor Role: collaborator

Stand Up To Cancer

OTHER

Sponsor Role: collaborator

Vanderbilt-Ingram Cancer Center

OTHER

Sponsor Role: lead

Responsible Party

Ingrid Mayer, MD

Principal Investigator

Responsibility Role: PRINCIPAL_INVESTIGATOR

Principal Investigators

Ingrid Mayer, MD

Role: PRINCIPAL_INVESTIGATOR

Vanderbilt-Ingram Cancer Center

Locations

Vanderbilt-Ingram Cancer Center

Nashville, Tennessee, United States

Countries

United States

Provided Documents

Document Type: Study Protocol and Statistical Analysis Plan

View Document

Other Identifiers

NCI-2018-01159

Identifier Type: REGISTRY

Identifier Source: secondary_id

VICC BRE 17107

Identifier Type: -

Identifier Source: org_study_id